[Federal Register: July 20, 2004 (Volume 69, Number 138)]
[Proposed Rules]               
[Page 43351-43366]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr20jy04-17]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 312, 314, 600, and 601

[Docket No. 2004N-0267]

 
Applications for Approval to Market a New Drug; Complete Response 
Letter; Amendments to Unapproved Applications

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
our regulations on new drug applications (NDAs) and abbreviated new 
drug applications (ANDAs) for approval to market new drugs and generic 
drugs. We propose to discontinue the use of approvable letters and not 
approvable letters when taking action on marketing applications. 
Instead, we intend to use complete response letters to indicate that 
the review cycle is complete and that the application is not ready for 
approval. We also are proposing to revise the regulations on extending 
the review cycle due to the submission of an amendment to an unapproved 
application and starting a new cycle after a resubmission following 
receipt of a complete response letter. In addition, we are proposing to 
add to the regulations on biologics license applications (BLAs) a 
provision on the issuance of complete response letters to BLA 
applicants. We are taking these actions to implement the user fee 
performance goals referenced in the Prescription Drug User Fee 
Amendments of 2002 that address procedures and establish target 
timeframes for reviewing human drug applications.

DATES: Submit written or electronic comments by October 18, 2004. See 
section VIII of this document for the proposed effective date of a 
final rule based on this document.

ADDRESSES: You may submit comments, identified by [Docket No. 2004N-
0267], by any of the following methods:
     Federal eRulemaking Portal: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov. 

Follow the instructions for submitting comments.
     Agency Web Site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments. 

Follow the instructions for submitting comments on the agency Web site.
     E-mail: fdadockets@oc.fda.gov. Include [Docket No. 2004N-
0267] in the subject line of your e-mail message.
     Fax: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the agency name 
and [Docket No. 2004N-0267] for this rulemaking. All comments received 
will be posted without change to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments, 

including any personal information provided. For detailed instructions 
on submitting comments and additional information on the rulemaking 
process, see the ``Request for Comments'' heading in the SUPPLEMENTARY 
INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments and/or 

the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.
    The Office of Management and Budget (OMB) is still experiencing 
significant delays in the regular mail, including first class and 
express mail, and messenger deliveries are not being accepted. To 
ensure that comments on the information collection are received, OMB 
recommends that written comments be faxed to the Office of Information 
and Regulatory Affairs, OMB, Attn: Fumie Yokota, Desk Officer for FDA, 
FAX: 202-395-6974.

FOR FURTHER INFORMATION CONTACT: Brian L. Pendleton, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-443-5523.

SUPPLEMENTARY INFORMATION:

I. Background

A. User Fee Performance Goals and Complete Response Letters

    In conjunction with the Prescription Drug User Fee Act of 1992 
(PDUFA) (Public Law 102-571), we committed to meet certain goals for 
reviewing and acting on human drug applications, as defined in section 
735(1) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
379g(1)). For example, we promised that by September 30, 1997, we would 
review and act on at least 90 percent of standard NDAs within 12 months 
after the submission date (H. Rep. No. 895, 102d Cong., 2d. sess. 32 
(1992) (letter from David A. Kessler, M.D., Commissioner of Food and 
Drugs, to Representatives John Dingell and Norman Lent, House Committee 
on Energy and Commerce (September 14, 1992))).
    FDA's drug application review performance goals were revised with 
the enactment of the Food and Drug Administration Modernization Act of 
1997 (Public Law 105-115) (the user fee provisions of this act are 
known as ``PDUFA II''). The goals were further revised in conjunction 
with the enactment of the Prescription Drug User Fee Amendments of 2002 
(PDUFA III), set forth in title V, subtitle A, of the Public Health 
Security and Bioterrorism Preparedness and Response Act of 2002 (Public 
Law 107-188). Section 502 of PDUFA III states that user fees will be 
dedicated to expediting the drug development process and the process 
for the review of human drug applications in accordance with the new 
performance goals, which are set forth in an enclosure to letters from 
Tommy Thompson, Secretary of Health and Human Services, to the Chairman 
of the House Committee on Energy and Commerce and the Ranking Member of 
the Senate Committee on Health, Education, Labor and Pensions (June 4, 
2002) (Goals Letter).
    Under the user fee performance goals, the term ``review and act 
on'' is defined as the issuance of a complete action letter after the 
complete review of a complete application that we have accepted for 
filing (Goals Letter at 15). An action letter, if not an approval, 
states the specific deficiencies of the application, and where 
appropriate, the actions necessary to place the application in 
condition for approval (id.).
    As part of the user fee performance goals (first in PDUFA II and 
again in PDUFA III), FDA's Center for Drug Evaluation and Research 
(CDER) and

[[Page 43352]]

Center for Biologics Evaluation and Research (CBER) agreed to revise 
their regulations and procedures to provide for the issuance of either 
an approval or a ``complete response'' action letter at the completion 
of the review cycle for an application (Goals Letter at 15). We are now 
proposing to revise our regulations on human drugs in part 314 (21 CFR 
part 314) to replace two types of action letters currently used, 
approvable letters (Sec.  314.110) and not approvable letters (Sec.  
314.120), with complete response letters. Because there are no 
provisions on action letters in the biological product regulations in 
parts 600 through 680 (21 CFR parts 600 through 680), CBER had only to 
change their standard operating procedures to incorporate the use of a 
complete response letter at the end of a review cycle for a biological 
product. Although CBER has already done this, we are now proposing to 
add a regulation (proposed Sec.  601.3) on the issuance of complete 
response letters concerning BLAs and BLA supplements.
    In replacing approvable and not approvable letters with complete 
response letters, our intent is to adopt a consistent and more neutral 
mechanism to convey that we cannot approve a drug marketing application 
in its current form. Historically, FDA issued a not approvable letter 
when deficiencies were major (e.g., no adequate and well-controlled 
studies, failure to demonstrate effectiveness, and a major safety 
concern). However, the distinction between approvable and not 
approvable letters became somewhat blurred. For example, in some cases, 
the absence of a second study supporting the effectiveness of a 
proposed drug product for a particular indication might have led to a 
not approvable letter; in other cases, FDA might have issued an 
approvable letter stating the need for additional evidence. Thus, 
issuance of an approvable letter might mean that an application needed 
only minor changes, such as a revision of labeling, or much more 
substantial changes. In addition, we subsequently approved many 
applications for which we had first issued a not approvable letter. 
Issuance of complete response letters will ensure a consistent approach 
to informing sponsors of needed changes before we can approve an 
application, with no implication as to the ultimate approvability of 
the application.
    We also intend to incorporate into the regulations for NDAs the 
terminology based on the user fee performance goals regarding Class 1 
and Class 2 resubmissions. A ``Class 1 resubmission'' is defined for 
performance goal purposes as an application resubmitted after receipt 
of an approvable or not approvable letter that includes only certain 
items such as draft or final printed labeling, safety or stability 
updates, or other minor clarifying information. A ``Class 2 
resubmission'' is one that addresses any other items, including any 
item that would require presentation to an advisory committee. A Class 
1 resubmission has a performance goal of 2 months and a Class 2 
resubmission has a performance goal of 6 months. In accordance with the 
user fee goals, we are proposing to apply this terminology to original 
NDAs as well as to efficacy supplements (supplements to approved 
applications to make certain significant changes to product labeling). 
As a result, efficacy supplements would be treated like original NDAs 
with regard to resubmissions. We are proposing to apply different rules 
to resubmissions of other types of NDA supplements.

B. ANDAs

    Although the user fee performance goals do not apply to ANDAs, the 
current regulations regarding approvable and not approvable letters in 
Sec. Sec.  314.110 and 314.120 apply to both NDAs and ANDAs (with a few 
exceptions). As a result, any proposed change to the regulations for 
NDAs must take into account the impact on ANDAs. Because we intend to 
change the regulations for NDAs and we believe that these changes make 
sense for other applications, we have decided to propose similar 
changes for ANDAs.

C. Amendments to Unapproved Applications

    The PDUFA performance goals also state that a major amendment to an 
unapproved application submitted within 3 months of the goal date 
(i.e., the end of the initial review cycle) extends the goal date by 3 
months. We are proposing to incorporate this provision into our 
regulations by revising Sec.  314.60 on amendments to unapproved 
applications. In accordance with the user fee goals, we are proposing 
to apply this provision to efficacy supplements and resubmissions of 
applications and efficacy supplements as well, but not to ANDAs.

II. Highlights of the Proposed Rule

A. Complete Response Letters

    In accordance with the PDUFA performance goals and in response to 
the concerns previously discussed, we are proposing to substitute 
complete response letters for approvable and not approvable letters at 
the completion of the review cycle for an NDA or ANDA. Under proposed 
Sec.  314.110, we will send a complete response letter if we determine 
that we will not approve an application or abbreviated application in 
its present form. The complete response letter usually would describe 
all of the specific deficiencies in the application or abbreviated 
application. If we determine, after an application is filed or an 
abbreviated application is received, that the data submitted are 
inadequate to support approval, we might issue a complete response 
letter without first conducting required inspections and/or reviewing 
proposed product labeling.
    Table 1 of this document summarizes the changes that we propose to 
make in substituting complete response letters for approvable and not 
approvable letters:

Table 1.--Summary of Proposed Changes Regarding Substitution of Complete
        Response Letter for Approvable and Not Approvable Letters
------------------------------------------------------------------------
        Current Regulations                  Proposed Regulations
------------------------------------------------------------------------
Approvable Letter for NDA            Complete Response Letter
------------------------------------------------------------------------
 States that NDA is           States that FDA will not
 basically approvable if certain      approve NDA or ANDA in its present
 issues are resolved.                 form.
------------------------------------------------------------------------
 Indicates that NDA           Describes all specific
 substantially meets requirements     deficiencies, except when issued
 of part 314 (21 CFR part 314) and    without conducting required
 FDA can approve it if applicant      inspections or labeling review
 submits additional information or    because data found to be
 agrees to specific conditions        inadequate to support approval.
 (e.g., labeling changes).
------------------------------------------------------------------------
Approvable Letter for ANDA           ...................................
------------------------------------------------------------------------

[[Page 43353]]


 Indicates that ANDA          Reflects complete review
 substantially meets requirements     of data in NDA or ANDA as well as
 of part 314 and is approvable if     amendments for which review cycle
 minor deficiencies are corrected.    was extended.
------------------------------------------------------------------------
 Describes deficiencies and   Where appropriate,
 states when applicant must           describes actions necessary to
 respond.                             place NDA or ANDA in condition for
                                      approval.
------------------------------------------------------------------------
Not Approvable Letter for NDA or     ...................................
 ANDA
------------------------------------------------------------------------
 States that NDA cannot be   ...................................
 approved for one of reasons in
 Sec.   314.125 or ANDA cannot be
 approved for one of reasons in
 Sec.   314.127.
------------------------------------------------------------------------
 Describes deficiencies in   ...................................
 NDA or ANDA.
------------------------------------------------------------------------

    For products for which approval of a BLA is required for marketing, 
we are proposing to adopt a new regulation, Sec.  601.3, stating that 
FDA will send a BLA a complete response letter if we determine that we 
will not approve the BLA or BLA supplement in its present form.

B. Resubmissions

    We also propose to revise the current provisions in Sec. Sec.  
314.110 and 314.120 on extension of the review period due to 
resubmission of an NDA or ANDA after receipt of an approvable or not 
approvable letter (to be replaced by a complete response letter). We 
propose that a Class 2 resubmission of an NDA following receipt of a 
complete response letter would start a new 6-month review cycle, as is 
the case with an ``amendment'' following receipt of a not approvable 
letter under current Sec.  314.120(a)(1). A Class 1 resubmission of an 
NDA following receipt of a complete response letter would start a new 
2-month review cycle.
    The proposed rules on Class 1 and Class 2 resubmissions would also 
apply to efficacy supplements to NDAs, in accordance with the user fee 
performance goals. We believe that this is appropriate because efficacy 
supplements, like original applications, contain varying amounts of 
data. Where extensive data requiring significant agency resources for 
review are provided, the current 6-month review cycle should apply. But 
as with some NDA resubmissions, it would be appropriate to consider 
some smaller resubmissions of efficacy supplements as Class 1 
resubmissions. We propose to apply different rules and terminology to 
other types of NDA supplements, including supplements dealing with 
chemistry, manufacturing, and controls (CMC) and labeling supplements 
for which no clinical data are needed. For NDA supplements other than 
efficacy supplements, a resubmission would start a new 6-month review 
cycle.
    A ``major'' resubmission of an ANDA following receipt of a complete 
response letter would start a new 6-month review cycle, as is the case 
with an ``amendment'' following receipt of a not approvable letter 
under current Sec.  314.120(a)(1). A ``minor'' resubmission of an ANDA 
would start a new review cycle of an unspecified length; the period 
might last from 30 days to a few months, depending on the issues 
involved. Under the relevant current CDER guidance document, entitled 
``Major, Minor, and Telephone Amendments to Abbreviated New Drug 
Applications'' (December 2001), a minor resubmission usually would 
start a new review cycle of between 30 to 60 days.
    The proposed changes to our regulations on applicants' responses to 
action letters are summarized in the following table 2.

     Table 2.--Summary of Proposed Changes to Regulations Regarding
      Applicant's Response to Agency Action Letter (Resubmissions)
------------------------------------------------------------------------
        Current Regulations                  Proposed Regulations
------------------------------------------------------------------------
Applicant's Response to Approvable   NDA or ANDA Applicant's Response to
 Letter or Not Approvable Letter      Complete Response Letter
 for NDA (or NDA Supplement)
------------------------------------------------------------------------
Within 10 days of date of letter,    Review period is extended until
 NDA applicant must do one of         applicant takes one of following
 following:                           actions:
------------------------------------------------------------------------
 Amend application or         Resubmit NDA or ANDA,
 notify FDA of intent to file         addressing identified
 amendment.                           deficiencies.
------------------------------------------------------------------------
 Withdraw application.       --Class 1 resubmission of NDA or
                                      efficacy supplement starts new, 2-
                                      month cycle
------------------------------------------------------------------------
 Request opportunity for     --Class 2 resubmission of NDA or
 hearing.                             efficacy supplement starts new, 6-
                                      month cycle
------------------------------------------------------------------------
 Agree to extend review      --Resubmission of NDA supplement
 period to decide which of above      other than efficacy supplement
 actions to take.                     starts new, 6-month cycle
------------------------------------------------------------------------
Response to Approvable Letter for    ...................................
 ANDA (or ANDA Supplement)
------------------------------------------------------------------------
 Correct deficiencies by     --Major resubmission of ANDA or
 specified date or FDA will refuse    ANDA supplement starts new, 6-
 to approve ANDA or ANDA              month cycle
 supplement.
------------------------------------------------------------------------

[[Page 43354]]


 Request opportunity for     --Minor resubmission of ANDA or
 hearing within 10 days.              ANDA supplement starts new cycle
                                      of variable length
------------------------------------------------------------------------
Response to Not Approvable Letter    ...................................
 for ANDA (or ANDA Supplement)
------------------------------------------------------------------------
 Same as for NDAs except      Withdraw NDA or ANDA.
 that 10-day period does not apply
 (with exception of request for
 opportunity for hearing).
------------------------------------------------------------------------
 FDA may regard failure to    Request opportunity for
 respond within 180 days as request   hearing.
 to withdraw.
------------------------------------------------------------------------

    These proposed changes with respect to NDAs are consistent with our 
user fee performance goals for resubmissions of human drug applications 
following receipt of an action letter. The proposed provisions for 
ANDAs are similar, although not identical, to those for NDAs.

C. Amendments to Unapproved Applications

    In accordance with our user fee goals, we are proposing to revise 
our regulations on extending the review cycle following the submission 
of an amendment to an unapproved NDA. Under current Sec.  314.60, the 
submission of a major amendment to an unapproved NDA (such as one that 
contains significant new data from a previously unreported study or 
detailed new analyses of earlier data) may extend the review period by 
up to 180 days. Under the user fee goals, a major amendment to an 
original NDA submitted within 3 months of the goal date extends the 
goal date by 3 months (Goals Letter at 15). Therefore, we propose to 
revise Sec.  314.60 to state that submission of a major amendment to an 
original NDA within 3 months of the end of the initial review cycle 
constitutes an agreement to extend the review cycle by 3 months. The 
proposed regulation states that FDA may instead defer review of such an 
amendment until the subsequent review cycle.
    Under the proposal, the submission of a major amendment to an NDA 
more than 3 months before the close of the initial review cycle, or the 
submission of a minor amendment during the initial review cycle, would 
not extend the review cycle. FDA might, at its discretion, review such 
an amendment during the initial review cycle or defer review until the 
subsequent review cycle. This proposed change to Sec.  314.60 would 
codify for all NDAs our current policy on extending the review cycle 
for amendments to unapproved NDAs that are subject to user fees.
    Also in accordance with the user fee goals, we are proposing to 
revise the regulations to provide that submission of a major amendment 
to an efficacy supplement to an approved application within 3 months of 
the end of the initial review cycle constitutes an agreement to extend 
the review cycle for the supplement by 3 months (although we could 
defer review to the subsequent cycle). It is appropriate to treat major 
amendments to efficacy supplements the same way as major amendments to 
original applications because their review requires significant agency 
resources. Amendments to other types of NDA supplements, however, will 
not extend the review cycle.
    An additional change that is consistent with the user fee goals 
would provide that the submission of a major amendment to a 
resubmission of an application or efficacy supplement within 3 months 
of the end of the initial review cycle constitutes an agreement to 
extend the review cycle by 3 months (again, we could elect to defer 
review). Because major amendments to these resubmissions generally 
require the review of substantial data, it is appropriate to treat them 
the same way as major amendments to original applications or efficacy 
supplements.
    We propose to make only minor revisions to the regulations on 
submitting amendments to unapproved ANDAs in Sec.  314.96. The proposed 
rule would clarify that an amendment to an ANDA submitted before the 
end of the initial review cycle that contains significant data or 
information could extend the initial review cycle by as many as 180 
days.
    Table 3 of this document summarizes the proposed changes to our 
regulations on amendments submitted before an action letter:

   Table 3.--Summary of Proposed Changes to Regulations on Amendments
                    Submitted Prior to Action Letter
------------------------------------------------------------------------
        Current Regulations                  Proposed Regulations
------------------------------------------------------------------------
Amendments to Unapproved NDAs and    Amendments to Unapproved NDAs and
 NDA Supplements                      Efficacy Supplements
------------------------------------------------------------------------
 Submission of major          Submission of major
 amendment constitutes agreement to   amendment within 3 months of end
 extend deadline for FDA decision.    of initial review cycle
                                      constitutes agreement to extend
                                      cycle by 3 months; FDA may instead
                                      defer review to subsequent cycle.
------------------------------------------------------------------------
 FDA may not extend review    Initial review cycle may
 period more than 180 days.           be extended only once for major
                                      amendment.
------------------------------------------------------------------------
 Submission of nonmajor       Submission of major
 amendment will not extend review     amendment more than 3 months
 period.                              before end of initial review cycle
                                      will not extend cycle.
------------------------------------------------------------------------
Amendments to Unapproved ANDAs and    Submission of minor
 ANDA Supplements                     amendment will not extend review
                                      cycle.
------------------------------------------------------------------------
 Submission of amendment     ...................................
 containing significant data or
 information constitutes agreement
 to extend review period up to 180
 days.
------------------------------------------------------------------------

[[Page 43355]]


 Same for amendments to      ...................................
 unapproved ANDA supplements.
------------------------------------------------------------------------
                                     Amendments to Unapproved NDA
                                      Supplements Other Than Efficacy
                                      Supplements
------------------------------------------------------------------------
                                      Submission of any
                                      amendment will not extend the
                                      initial review cycle.
------------------------------------------------------------------------
                                     Amendments to Resubmissions of
                                      Applications and Efficacy
                                      Supplements
------------------------------------------------------------------------
                                      Submission of major
                                      amendment within 3 months of end
                                      of initial review cycle
                                      constitutes agreement to extend
                                      cycle by 3 months; FDA may instead
                                      defer review to subsequent cycle.
------------------------------------------------------------------------
                                     Amendments to Unapproved ANDAs and
                                      ANDA Supplements
------------------------------------------------------------------------
                                      Unchanged
------------------------------------------------------------------------

III. Description of the Proposed Rule

    The proposed rule would make the following five types of revisions 
and additions to the regulations: (1) Revisions to remove the use of 
approvable and not approvable letters for NDAs and ANDAs and to 
incorporate the use of complete response letters and use of the term 
``review cycle'', (2) addition of provisions on the issuance of 
complete response letters concerning BLAs and BLA supplements, (3) 
revisions related to resubmissions of NDAs and ANDAs after receipt of 
complete response letters, (4) miscellaneous technical revisions 
related to the use of complete response letters for NDAs and ANDAs, and 
(5) revisions related to amendments to unapproved NDAs and ANDAs.

A. The Complete Response Letter and the Review Cycle for NDAs and ANDAs

1. Definitions (Proposed Sec.  314.3)
    Current Sec.  314.3(b) defines ``approvable letter'' and ``not 
approvable letter.'' We propose to revise Sec.  314.3(b) by removing 
these definitions and adding a definition of ``complete response 
letter.'' A complete response letter would be defined as a written 
communication to an applicant from FDA usually identifying all of the 
deficiencies in an application or abbreviated application that must be 
satisfactorily addressed before it can be approved. (Under current 
Sec.  314.3, ``application'' refers to an NDA and ``abbreviated 
application'' refers to an ANDA.)
    We also propose to revise Sec.  314.3(b) by adding a definition of 
``original application.'' An original application would be defined as a 
pending application for which we have never issued a complete response 
letter or approval letter or an application that was submitted again 
after we had refused to file it or after it was withdrawn without being 
approved.
    We also propose to add definitions of ``Class 1 resubmission'' and 
``Class 2 resubmission'' for resubmissions of NDAs. A ``Class 1 
resubmission'' would be defined as the resubmission of an application 
(i.e., an NDA), following receipt of a complete response letter, that 
contains final printed labeling, draft labeling, certain safety 
updates, stability updates to support provisional or final dating 
periods, commitments to perform Phase 4 studies (including proposals 
for such studies), assay validation data, final release testing on the 
last lots used to support approval, minor reanalyses of previously 
submitted data, and other comparatively minor information.\1\ A ``Class 
2 resubmission'' would be defined as the resubmission of an 
application, following receipt of a complete response letter, that 
includes any item not specified in the definition of ``Class 1 
resubmission,'' including any item that would require presentation to 
an advisory committee. These definitions of Class 1 and Class 2 
resubmissions of NDAs reflect those stated in the Goals Letter and will 
not be applied to ANDAs.
---------------------------------------------------------------------------

    \1\ This definition of Class 1 resubmission matches the 
definition stated in the user fee Goals Letter, except that the 
latter refers to ``other minor clarifying information'' and states 
that ``[o]ther specific items may be added later as the Agency gains 
experience with the scheme and will be communicated via guidance 
documents to industry'' (Goals Letter at 16). The proposed 
definition would allow resubmissions that contain unspecified 
information of a comparatively minor nature to be treated as Class 1 
resubmissions. FDA might address specific types of such 
resubmissions in agency guidance.
---------------------------------------------------------------------------

    In addition, we propose to revise Sec.  314.3(b) to add a 
definition of ``efficacy supplement.'' An ``efficacy supplement'' would 
be defined as a supplement to an approved NDA to make one or more of 
the following changes to product labeling: (1) Add or modify an 
indication for use, (2) revise the dose or dose regimen, (3) provide 
for a new route of administration, (4) make a comparative efficacy 
claim naming another drug product, (5) significantly alter the intended 
patient population, (6) change the marketing status from prescription 
to over-the-counter use, (7) complete the traditional approval of a 
product originally approved under subpart H of part 314, or (8) 
incorporate other information based on at least one adequate and well-
controlled clinical study.
2. Timeframes for Review (Proposed Sec.  314.100)
    Current Sec.  314.100 addresses the timeframes for reviewing 
applications and abbreviated applications. Section 314.100(a) states 
that within 180 days of receipt of an application for a new drug under 
section 505(b) of the act (21 U.S.C. 355(b)) or of an abbreviated 
application for a new drug under section 505(j) of the act, FDA will 
review it and send the applicant either an approval letter under Sec.  
314.105, an approvable letter under Sec.  314.110, or a not approvable 
letter under Sec.  314.120. This 180-day period is called the review 
clock.
    We propose to revise Sec.  314.100(a) by creating two separate 
provisions reflecting different review cycles for applications that are 
subject to user fees and those that are not subject to such fees. 
Proposed Sec.  314.100(a)(1) states that, except as provided in

[[Page 43356]]

Sec.  314.100(a)(2), within 180 days of receipt of an application for a 
new drug under section 505(b) of the act or of an abbreviated 
application for a new drug under section 505(j) of the act, FDA will 
review it and send the applicant either an approval letter under Sec.  
314.105 or a complete response letter under Sec.  314.110. We propose 
to rename this 180-day period the ``initial review cycle'' to be 
consistent with the term we currently use.
    Proposed Sec.  314.100(a)(2) states that, for applications that are 
human drug applications, as defined in section 735(1)(A) and (B) of the 
act (NDAs), or supplements to such applications, as defined in section 
735(2) of the act, the initial review cycle will be adjusted to be 
consistent with our user fee performance goals for reviewing such 
applications and supplements. We are making this change to reflect 
that, under the user fee performance goals, we are not expected to 
review and act on all applications that are subject to user fees within 
180 days of receipt of such applications. Rather, we have committed to 
take action on certain percentages of applications within different 
time periods, depending on the type of application (e.g., standard, 
priority, supplement, resubmission) and the relevant fiscal year (see 
Goals Letter at 1, 2, and 3). In some cases, such as CMC supplements 
that require prior approval, we have committed to taking action in less 
than 180 days. Consequently, proposed Sec.  314.100(a)(2) reflects that 
the initial review cycle for human drug applications and supplements to 
such applications may in some cases be shorter or longer than 180 days.
    Current Sec.  314.100(b) states that, during the review period, an 
applicant may withdraw an application under Sec.  314.65 or an 
abbreviated application under Sec.  314.99 and later resubmit it. We 
will treat the subsequent submission as a new original application or 
abbreviated application. Current Sec.  314.100(b) uses the term 
``review period'' rather than ``review clock'' because it is intended 
to address withdrawals made at any time while an application or 
abbreviated application is pending before the agency (i.e., filed but 
not yet approved), not simply withdrawals made while the review clock 
is running. (Although not defined in the regulations, the ``review 
period'' means the period from filing of an NDA or receipt of an ANDA 
to the ultimate disposition of the application, either by approval, 
refusal to approve the NDA under Sec.  314.125 or the ANDA under Sec.  
314.127, or withdrawal of the application.) Rather than use the term 
``review period'' or ``review clock,'' we propose to clarify Sec.  
314.100(b) by stating that, at any time before approval, an applicant 
may withdraw an application under Sec.  314.65 or an abbreviated 
application under Sec.  314.99 and later submit it again for 
consideration. We propose to substitute the phrase ``submit it again'' 
for ``resubmit it'' because we want to limit the terms ``resubmit'' and 
``resubmission'' in part 314 to resubmissions after receipt of a 
complete response letter.
    Current Sec.  314.100(c) states that the review clock may be 
extended by mutual agreement between FDA and an applicant or as 
provided in Sec. Sec.  314.60 or 314.96, as the result of a major 
amendment. To be consistent with proposed Sec.  314.100(a)(1), we 
propose to revise this provision by substituting ``initial review 
cycle'' for ``review clock.''
3. Filing an NDA and Receiving an ANDA (Proposed Sec.  314.101)
    Current Sec.  314.101(f)(1) states that within 180 days after the 
date of filing of an NDA, plus the period of time the review period was 
extended (if any), FDA will either approve the application or issue a 
notice of opportunity for hearing if the applicant asked FDA to provide 
it an opportunity for a hearing on an application in response to an 
approvable letter or a not approvable letter.
    Consistent with our proposed revision of Sec.  314.100(a), we are 
proposing to add a new Sec.  314.101(f)(2) (redesignating current Sec.  
314.101(f)(2) and (f)(3) as Sec.  314.101(f)(3) and (f)(4), 
respectively). The new section states that for applications that are 
human drug applications, as defined in section 735(1)(A) and (B) of the 
act, and supplements to such applications, as defined in section 735(2) 
of the act, the 180-day period specified in Sec.  314.101(f)(1) will be 
adjusted to be consistent with the agency's user fee performance goals 
for reviewing such applications and supplements. We also propose to 
replace references in current Sec.  314.101(f) to approvable and/or not 
approvable letters with references to complete response letters.
4. Approvable and Not Approvable Letters (Proposed Sec. Sec.  314.110 
and 314.120)
    Current Sec.  314.110 sets forth provisions on the issuance of and 
response to approvable letters. Section 314.110(a) states that it may 
be appropriate for FDA to issue an approvable letter at the end of a 
review period to inform an applicant that its application or 
abbreviated application is basically approvable if the applicant 
resolves certain issues. It also states that an approvable letter 
signifies that we believe that we can approve the application or 
abbreviated application if the applicant submits specific additional 
information or material or agrees to specific conditions (e.g., changes 
in labeling). Section 314.110(a) further states that as a practical 
matter, an approvable letter in most instances serves as a mechanism 
for resolving outstanding issues on drugs that are about to be approved 
and marketed.
    Current Sec.  314.120 addresses the agency's issuance of not 
approvable letters to applicants and applicants' responses to such 
letters. Section 314.120(a) states that we will send an applicant a not 
approvable letter if we believe that the application may not be 
approved for one of the reasons given in Sec.  314.125, or that an 
abbreviated application may not be approved for one of the reasons 
given in Sec.  314.127.
    We propose to revise Sec.  314.110 (and to remove and reserve Sec.  
314.120) by replacing references to approvable letters and not 
approvable letters with references to complete response letters.
    a. Issuance of complete response letters. Proposed Sec.  314.110 is 
entitled ``Complete response letter to the applicant.'' Proposed Sec.  
314.110(a) states that we will send the applicant a complete response 
letter if we determine that we will not approve the application or 
abbreviated application in its present form for one or more of the 
reasons given in Sec.  314.125 or Sec.  314.127, respectively.
    Proposed Sec.  314.110(a)(1) states that a complete response letter 
will describe all of the specific deficiencies in the application or 
abbreviated application, except as stated in proposed Sec.  
314.110(a)(3). (Under current procedures, we might also notify the 
applicant of deficiencies in certain parts of the application or 
abbreviated application before issuance of a complete response letter.)
    Following issuance of a complete response letter, we would not 
expect to identify any additional deficiencies in an NDA or ANDA. 
However, it is possible that we might find additional deficiencies in 
an application following review of: (1) Data submitted in an amendment 
not reviewed before issuance of the complete response letter, (2) a 
resubmission containing new data or analyses, or (3) additional safety 
data obtained from any source. These additional deficiencies might be 
based wholly on the newly submitted data or might reflect new analyses 
of previous data prompted by the new data. Finally, it is also possible 
that we might find

[[Page 43357]]

additional deficiencies in previously reviewed data on the basis of 
advice from an advisory committee.
    Proposed Sec.  314.110(a)(2) states that the complete response 
letter reflects FDA's complete review of the data submitted in an 
original application or abbreviated application (or, where appropriate, 
a resubmission) and any amendments for which the review cycle was 
extended. It adds that the complete response letter will identify any 
amendments for which the review cycle was not extended that we have not 
yet reviewed.
    Proposed Sec.  314.110(a)(3) states that if we determine, after an 
application is filed or an abbreviated application is received, that 
the data submitted are inadequate to support approval, we might issue a 
complete response letter without first conducting required inspections 
and/or reviewing proposed product labeling.
    Proposed Sec.  314.110(a)(4) states that, where appropriate, a 
complete response letter will describe the actions necessary to place 
the application or abbreviated application in condition for approval.
    b. Responses to complete response letters. Current Sec.  314.110(a) 
states that within 10 days after the date of an approvable letter, the 
sponsor of an NDA must respond in one of the following several ways: 
(1) Amend the application (or notify us of an intent to do so), (2) 
withdraw the application (failure to respond within 10 days to an 
approvable letter is regarded as a request to withdraw the 
application), (3) ask us to provide the applicant with an opportunity 
for a hearing on whether there are grounds for denying the approval of 
the application under section 505(d) of the act, or (4) notify us that 
the applicant agrees to extend the review period under section 505(c) 
of the act so that the applicant can determine whether to take one of 
the previously listed actions.
    Current Sec.  314.110(b) addresses the issuance of approvable 
letters to ANDA applicants. Under Sec.  314.110(b), we will send an 
ANDA applicant an approvable letter only if the abbreviated application 
substantially meets the requirements of part 314 and we believe that we 
can approve it if minor deficiencies (e.g., regarding labeling) are 
corrected. The approvable letter describes the deficiencies in the ANDA 
and states a date by which the applicant must respond. Unless the 
applicant corrects the deficiencies within the specified period, FDA 
will refuse to approve the ANDA. Within 10 days of the date of the 
approvable letter, the applicant may request an opportunity for a 
hearing.
    In proposed Sec.  314.110(b), we direct both NDA and ANDA 
applicants to take one of three actions following receipt of a complete 
response letter, eliminating (except with respect to resubmissions) the 
separate provisions for ANDAs in current Sec.  314.110(b). We also 
propose to delete the requirement that NDA applicants take action 
within 10 days.
    The first option for the recipient of a complete response letter, 
stated in proposed Sec.  314.110(b)(1), is to resubmit the application 
or abbreviated application, addressing all deficiencies identified in 
the letter. For purposes of Sec.  314.110, a resubmission would mean 
the submission by an applicant of all materials needed to fully address 
all deficiencies identified in the complete response letter.
    Under proposed Sec.  314.110(b)(1)(i), a resubmission of an NDA or 
an efficacy supplement that we classify as a Class 1 resubmission would 
constitute an agreement by the applicant to start a new 2-month review 
cycle beginning on the date we receive the resubmission. Under proposed 
Sec.  314.110(b)(1)(ii), a resubmission of an NDA or an efficacy 
supplement that we classify as a Class 2 resubmission would constitute 
an agreement by the applicant to start a new 6-month review cycle 
beginning on the date we receive the resubmission.
    For NDA supplements other than efficacy supplements, such as a 
supplement for a change in CMC or a labeling supplement that does not 
require clinical data, we propose to retain the current practice of not 
applying the Class 1 and Class 2 terminology and review cycle lengths. 
Thus, under proposed Sec.  314.110(b)(1)(iii), a resubmission of an NDA 
supplement other than an efficacy supplement would constitute an 
agreement by the applicant to start a new 6-month review cycle 
beginning on the date we receive the resubmission.
    For resubmissions of ANDAs, we propose to continue the current 
practice of categorizing them as ``major'' or ``minor.'' Under proposed 
Sec.  314.110(b)(1)(iv), a major resubmission of an ANDA would 
constitute an agreement by the applicant to start a new 6-month review 
cycle beginning on the date we receive the resubmission. Under proposed 
Sec.  314.110(b)(1)(v), a minor resubmission of an ANDA would 
constitute an agreement to start a new review cycle (length 
unspecified) beginning on the date we receive the resubmission. The 
actual length of the cycle would depend on the contents of the 
resubmission. As noted in section II.C of this document, CDER's 
guidance on ``Major, Minor, and Telephone Amendments to Abbreviated New 
Drug Applications'' provides guidance on how the agency handles these 
resubmissions. The guidance states that CDER attempts to review most 
minor amendments within 30 to 60 days, and we intend to apply this to 
minor resubmissions of ANDAs. Under the proposed rule, resubmissions of 
supplements to approved ANDAs would continue to be treated the same as 
ANDA resubmissions in accordance with Sec.  314.97.
    The second option for the recipient of a complete response letter, 
stated in proposed Sec.  314.110(b)(2), is to withdraw the application 
or abbreviated application. A decision to withdraw an application or 
abbreviated application would be without prejudice to a subsequent 
submission.
    The third option for the recipient of a complete response letter, 
stated in proposed Sec.  314.110(b)(3), is to ask us to provide the 
applicant an opportunity for a hearing on the question of whether there 
are grounds for denying approval of the application or abbreviated 
application under section 505(d) or (j)(4) of the act, respectively. 
Within 60 days of the date of a request for an opportunity for a 
hearing, or within a different time period to which we and the 
applicant agree, we would take either of the following actions: (1) 
Approve the application or abbreviated application under Sec.  314.105 
or (2) refuse to approve the NDA under Sec.  314.125 or the ANDA under 
Sec.  314.127 and give the applicant written notice of an opportunity 
for a hearing under Sec.  314.200 and section 505(c)(1)(B) or (j)(5)(C) 
of the act on the question of whether there are grounds for denying 
approval of the application.
    Under proposed Sec.  314.110(c), an applicant agrees to extend the 
review period under section 505(c)(1) of the act until it takes any of 
the actions listed in proposed Sec.  314.110(b). Section 505(c)(1) of 
the act directs FDA, within 180 days after the filing of an application 
under section 505(b) of the act or an additional period agreed upon by 
the applicant and the agency, to either approve the application (if we 
find that none of the grounds for denying approval stated in section 
505(d) of the act applies) or give the applicant an opportunity for a 
hearing under section 505(d) on the question of whether such 
application is approvable. Thus, the addition of the provision on 
agreement to extend the review period in proposed Sec.  314.110(c) 
would ensure that, if we do not approve an application, the applicant 
is provided a notice of opportunity for a hearing within the time 
specified by section 505(c)(1) of the act.

[[Page 43358]]

    Proposed Sec.  314.110(c) further states that we may consider an 
NDA applicant's failure to take any of the actions listed in Sec.  
314.110(b) within 1 year after receiving a complete response letter to 
be a request by the applicant to withdraw the application. However, 
regarding ANDAs, proposed Sec.  314.110(c) states that we may consider 
an applicant's failure to take any of the listed actions within 6 
months after receiving a complete response letter to be a request by 
the applicant to withdraw the abbreviated application. We believe that 
the shorter time period for ANDAs is appropriate because an ANDA 
resubmission is not likely to involve generation of clinical data and 
deficiencies normally could be addressed within 6 months.
    Because we propose to revise current Sec.  314.110 to state the 
provisions on complete response letters, we propose to delete current 
Sec.  314.120 on not approvable letters and to reserve this section for 
future use.

B. Complete Response Letter for BLAs

    To incorporate into the biologics regulations the use of complete 
response letters for BLAs, we are proposing to add a definition of 
``complete response letter'' to Sec.  600.3 and to add Sec.  601.3 on 
complete response letters.
1. Definition (Proposed Sec.  600.3)
    We propose to add to current Sec.  600.3, paragraph (jj) to define 
a complete response letter. Under proposed Sec.  600.3(jj), a complete 
response letter would be defined as a written communication to an 
applicant from FDA usually identifying all of the deficiencies in a 
biologics license application or supplement that must be satisfactorily 
addressed before it can be approved. (Current Sec.  600.3(gg) defines a 
``supplement'' as a request to the Director, Center for Biologics 
Evaluation and Research, to approve a change in an approved license 
application.)
2. Complete Response Letter to the Applicant (Proposed Sec.  601.3)
    To incorporate current CBER policy into the regulations, we are 
proposing to establish a new Sec.  601.3 on complete response letters. 
Under proposed Sec.  601.3(a), FDA will send the biologics license 
applicant or supplement applicant a complete response letter if we 
determine that we will not approve the biologics license application or 
supplement in its present form.
    Under proposed Sec.  601.3(b), a biologics license applicant or 
supplement applicant must take one of two actions after receiving a 
complete response letter. Under proposed Sec.  601.3(b)(1), the license 
or supplement applicant may resubmit the application or supplement, 
addressing all deficiencies identified in the complete response letter. 
Under proposed Sec.  601.3(b)(2), the license or supplement applicant 
may withdraw the application or supplement; a decision to withdraw 
would be without prejudice to a subsequent submission.
    Finally, under proposed Sec.  601.3(c), FDA may consider a 
biologics license applicant or supplement applicant's failure to either 
resubmit or withdraw the application or supplement within 1 year after 
receiving a complete response letter to be a request by the applicant 
to withdraw the application or supplement.

C. Miscellaneous Revisions Related to Adoption of Complete Response 
Letters for NDAs and ANDAs

    To reflect FDA's use of complete response letters for NDAs and 
ANDAs, the agency proposes to make the following additional revisions 
to its regulations:
1. Content and Format of Applications (Proposed Sec.  314.50)
    Current Sec.  314.50 specifies the content and format of NDAs. 
Section 314.50(d) describes the technical sections required in each 
application. Section 314.50(d)(5)(vi)(b) states that an applicant 
periodically must update its pending application with new safety 
information that might affect the statement of contraindications, 
warnings, precautions, and adverse reactions in the draft labeling. The 
applicant must file these safety update reports 4 months after the 
initial submission, after receiving an approvable letter, and when 
otherwise requested by FDA.
    We propose to revise Sec.  314.50(d)(5)(vi)(b) by replacing the 
requirement to submit a safety update report following receipt of an 
approvable letter with a requirement to submit a safety update report 
in a resubmission following receipt of a complete response letter. This 
would ensure that we have more extensive safety information than was 
available at the time of the original submission. In addition, we 
could, if appropriate, require submission of a safety update report 
immediately before issuing an approval letter under the current 
provision that allows us to require submission of a report ``at other 
times as requested by FDA.''
2. Withdrawal by the Applicant of an Unapproved Application (Proposed 
Sec.  314.65)
    Current Sec.  314.65 states that an applicant may at any time 
withdraw an application that is not yet approved by notifying us in 
writing. It further states that we will consider an applicant's failure 
to respond within 10 days to an approvable letter under Sec.  314.110 
or a not approvable letter under Sec.  314.120 to be a request by the 
applicant to withdraw the application.
    We propose to revise Sec.  314.65 to delete the reference to 
responding within 10 days to an approvable or not approvable letter, 
consistent with proposed Sec.  314.110. In addition, we propose to add 
a statement that if, by the time we receive a notice of withdrawal, we 
have identified any deficiencies in the application, we will list those 
deficiencies in the letter we send the applicant acknowledging the 
withdrawal.
3. Communications Between FDA and Applicants (Proposed Sec.  314.102)
    Current Sec.  314.102 addresses communications between FDA and 
applicants. Section 314.102(b) states that FDA reviewers shall make 
every reasonable effort to communicate promptly to applicants easily 
correctable deficiencies found in an application or an abbreviated 
application when those deficiencies are discovered, particularly 
deficiencies concerning CMC issues. This early communication is 
intended to permit applicants to correct readily identified 
deficiencies relatively early in the review process and to submit an 
amendment before the review period has elapsed. Section 314.102(b) 
further states that such early communication would not ordinarily apply 
to major scientific issues; instead, major scientific issues will 
ordinarily be addressed in an action letter.
    We propose to revise Sec.  314.102(b) to clarify that major 
scientific issues will ordinarily be addressed in a complete response 
letter, even though they may have been addressed earlier in a 
discipline review letter in accordance with user fee performance goals.
    Current Sec.  314.102(d) discusses end-of-review conferences. It 
states that at the conclusion of our review of an application or 
abbreviated application as designated by the issuance of an approvable 
or not approvable letter, we will provide applicants with an 
opportunity to meet with agency reviewing officials. The purpose of the 
meeting will be to discuss what further steps need to be taken by the 
applicant

[[Page 43359]]

before the application or abbreviated application can be approved. 
Section 314.102(d) further states that this meeting will be available 
on all applications or abbreviated applications, with priority given to 
applications for new chemical entities and major new indications for 
marketed drugs and for the first duplicates for such drugs. Requests 
for such meetings must be directed to the director of the division 
responsible for reviewing the application or abbreviated application.
    We propose to revise Sec.  314.102(d) by replacing ``an approvable 
or not approvable letter'' with ``a complete response letter.'' In 
addition, we propose to delete the references to abbreviated 
applications because the Office of Generic Drugs, which reviews such 
applications, does not routinely provide end-of-review conferences for 
ANDAs. Finally, because we virtually always agree to requests for end-
of-review conferences for NDAs and do not prioritize the scheduling of 
such conferences for particular types of NDAs, we propose to remove the 
reference to priority status for certain types of NDAs.
4. Approval (Proposed Sec.  314.105)
    Current Sec.  314.105(b), concerning approval of applications and 
abbreviated applications, states that FDA will approve an application 
and issue the applicant an approval letter (rather than an approvable 
letter under Sec.  314.110) on the basis of draft labeling if only 
minor labeling deficiencies remain. We propose to delete the reference 
to approvable letters. Substituting a reference to complete response 
letters would not be appropriate because issuance of such a letter 
would not necessarily signify that we believe that an application is 
basically approvable provided that certain issues are resolved or that 
the application substantially meets the requirements of part 314, as is 
the case with approvable letters issued under current Sec.  314.110.
5. Public Disclosure of Existence of Applications (Proposed Sec.  
314.430)
    Current Sec.  314.430(b) states that we will not publicly disclose 
the existence of an application or abbreviated application before we 
send an approvable letter to the applicant unless the existence of the 
application or abbreviated application has been previously publicly 
disclosed or acknowledged. The provision further states that CDER will 
maintain and make available for public disclosure a list of 
applications or abbreviated applications for which we have sent an 
approvable letter to the applicant.
    We propose to revise Sec.  314.430(b) to allow for FDA disclosure 
of the existence of an NDA or ANDA after issuance of an approval letter 
or tentative approval letter. Proposed Sec.  314.430 (b) states that we 
will not publicly disclose the existence of an application or 
abbreviated application before we send the applicant an approval letter 
under Sec.  314.105 or a tentative approval letter under Sec.  314.107, 
unless the existence of the application or abbreviated application has 
been previously publicly disclosed or acknowledged. We do not believe 
that it is necessary to include a provision stating that the agency 
will maintain and make available for public disclosure a list of 
approved applications and abbreviated applications because we already 
make this information available by routinely announcing the approval of 
NDAs and ANDAs within days of their approval and publishing an annual 
list (with monthly supplements) of ``Approved Drug Products With 
Therapeutic Equivalence Evaluations'' (known as the ``Orange Book'').
    We issue a tentative approval letter when an application meets the 
scientific and technical requirements for approval under section 505(b) 
or (j) of the act but marketing exclusivity (e.g., pediatric 
exclusivity, orphan drug exclusivity) or patent rights prevent final 
approval of the drug product. As stated in Sec.  314.107(b)(3)(v), 
tentative approval of an application does not constitute an approval of 
an application and cannot, absent a final approval letter from the 
agency, result in an effective approval of an application. However, 
because we only issue tentative approval letters when an application 
has met the scientific and technical approval requirements, tentative 
approval letters do not present the same disclosure concerns as 
correspondence regarding other unapproved applications. Therefore, we 
intend to follow our past practice of acknowledging the existence of 
applications that have received tentative approval letters and making 
those letters publicly available.
    Because current Sec.  314.107(b)(3) does not explicitly refer to 
our practice of issuing a letter notifying an applicant of a tentative 
approval, we propose to revise Sec.  314.107(b)(3)(v) to state that we 
will issue a tentative approval letter when tentative approval is 
appropriate in accordance with Sec.  314.107 (b)(3).
    The changes that we are proposing to the disclosure provisions 
would mean that FDA disclosure of the existence of an NDA or ANDA might 
result in later disclosure than sometimes occurs under the current 
regulation (i.e., with respect to those applications for which FDA now 
issues approvable letters). However, we believe that this effect would 
be limited because most applicants (at least for NDAs) publicly reveal 
the existence of their applications before agency issuance of an 
approval letter. Moreover, the proposed change would be consistent with 
the agency's long-standing presumption that, before approval (and 
absent evidence to the contrary), the existence of an application is 
confidential commercial information under 21 CFR 20.61. For example, 
under Sec.  601.51, FDA will not disclose the existence of a biological 
product file before a BLA has been approved unless it has previously 
been publicly disclosed or acknowledged.
    However, we specifically invite comment on whether it would be 
appropriate for FDA to disclose the existence of an NDA or ANDA 
following issuance of a complete response letter and if so, what 
conditions, if any, should be placed on such disclosure. For example, 
one alternative to the proposed approach would be that FDA would 
publicly disclose the existence of an NDA or ANDA following issuance of 
a complete response letter unless the applicant notified the agency (by 
some specified deadline) that the applicant had not publicly disclosed 
or acknowledged the existence of the application or abbreviated 
application. This approach would allow applicants to prevent agency 
disclosure of the existence of an application despite the issuance of a 
complete response letter. However, it also would create the potential 
for inadvertent disclosure and necessitate the establishment of a 
system to record and track applicants' positions regarding disclosure. 
This could be burdensome to applicants and the agency.
6. Other Technical Revisions (Proposed Sec. Sec.  312.84, 314.103, 
314.125, and 314.440)
    We are proposing to revise other sections of the regulations to 
replace references to approvable and/or not approvable letters with 
references to complete response letters. These revisions would be made 
to Sec.  312.84 (Risk-benefit analysis in review of marketing 
applications for drugs to treat life-threatening and severely-
debilitating illnesses), Sec.  314.103 (Dispute resolution), Sec.  
314.125 (Refusal to approve an application), and Sec.  314.440 
(Addresses for applications and abbreviated applications). (The 
proposed rule also revises this section by providing the current 
address to

[[Page 43360]]

which an NDA must be submitted and the address for applications 
regarding certain products reviewed by CBER.)

D. Amendments to Unapproved NDAs, ANDAs, and Unapproved Supplements to 
Approved NDAs

    The other principal purpose of this proposed rule, besides the 
adoption of complete response letters and related changes to 
resubmissions, is to revise the regulations in Sec. Sec.  314.60 and 
314.96 on amendments to unapproved NDAs and ANDAs, respectively.
1. Amendments to Unapproved NDAs, Supplements, and Resubmissions 
(Proposed Sec.  314.60)
    Amendments to unapproved NDAs are addressed in Sec.  314.60. 
Current Sec.  314.60(a) states that except as provided in Sec.  314.60 
(b), the applicant may submit an amendment to an application that is 
filed under Sec.  314.100, but not yet approved. (The reference to 
Sec.  314.100 is in error; Sec.  314.101 not Sec.  314.100 addresses 
the filing of applications.) Section 314.60(a) further states that the 
submission of a major amendment (e.g., one that contains significant 
new data from a previously unreported study or detailed new analyses of 
earlier data) constitutes an agreement by the applicant under section 
505(c) of the act to extend the date by which we are required to decide 
on the application. The section adds that we ordinarily will extend the 
review period but only for the time needed to review the new 
information, and we may not extend the period for more than 180 days. 
If we extend the review period for the application, the director of the 
division responsible for reviewing the application will notify the 
applicant of the length of the extension. The submission of an 
amendment that is not a major amendment will not extend the review 
period.
    We propose to revise Sec.  314.60(a) to state that we generally 
assume that when an original application (i.e., original NDA) 
supplement to an approved application or resubmission of an application 
or supplement is submitted to the agency for review, the applicant 
believes that we can approve the application, supplement, or 
resubmission as submitted. However, the applicant may submit an 
amendment to an application or supplement that has been filed under 
Sec.  314.101 but is not yet approved.
    In place of the provisions in current Sec.  314.60(a), we propose 
to add new Sec.  314.60(b). Under proposed Sec.  314.60(b)(1), 
submission of a major amendment to an original application, efficacy 
supplement, or resubmission of an application or efficacy supplement 
within 3 months of the end of the initial review cycle constitutes an 
agreement by the applicant under section 505(c) of the act to extend 
the review cycle by 3 months. However, the proposed regulation states 
that we may instead defer review of such an amendment until the 
subsequent review cycle. The subsequent review cycle would run from the 
resubmission of the application, efficacy supplement, or resubmission 
following receipt of the complete response letter to the issuance of 
either a second complete response letter or an approval letter. Under 
proposed Sec.  314.60(b)(1), if we extend the initial review cycle for 
an original application, efficacy supplement, or resubmission of an 
application or efficacy supplement under this paragraph (b)(1), the 
division responsible for reviewing the application, supplement, or 
resubmission will notify the applicant of the extension. Proposed Sec.  
314.60(b)(1) further states that the initial review cycle for an 
original application, efficacy supplement, or resubmission of an 
application or efficacy supplement may be extended only once due to 
submission of a major amendment. Finally, proposed Sec.  314.60(b)(1) 
states that we may, at our discretion, review any subsequent major 
amendment during the initial review cycle (as extended) or defer review 
until the subsequent review cycle.
    Under proposed Sec.  314.60(b)(2), submission of a major amendment 
to an original application, efficacy supplement, or resubmission of an 
application or efficacy supplement more than 3 months before the end of 
the initial review cycle will not extend the cycle. We may, at our 
discretion, review such an amendment during the initial review cycle or 
defer review until the subsequent review cycle.
    Under proposed Sec.  314.60(b)(3), submission of a minor amendment 
to an original application, efficacy supplement, or resubmission of an 
application or efficacy supplement will not extend the initial review 
cycle. We may, at our discretion, review such an amendment during the 
initial review cycle or defer review until the subsequent review cycle.
    Under proposed Sec.  314.60(b)(4), submission of an amendment to a 
supplement other than an efficacy supplement will not extend the 
initial review cycle. We may, at our discretion, review such an 
amendment during the initial review cycle or defer review until the 
subsequent review cycle.
    Proposed Sec.  314.60 (b)(5) specifies that a major amendment may 
not include data to support an indication for a use that was not 
included in the original application, supplement, or resubmission.
    These proposed regulations would codify for all NDAs, efficacy 
supplements, and resubmissions of NDAs and efficacy supplements, our 
current policy on extending the review period for human drug 
applications when a major amendment is submitted before FDA issuance of 
an action letter. As stated in the previous paragraphs, we believe that 
it is appropriate to treat amendments to unapproved efficacy 
supplements and amendments to resubmissions of applications and 
efficacy supplements, the same as amendments to unapproved NDAs. 
Amendments to ANDAs submitted before FDA issuance of an action letter 
are addressed in Sec.  314.96, discussed in section III.D.3 of this 
document.
2. Procedures for Submission of a Supplement to an Approved Application 
(Proposed Sec.  314.71)
    The references to different types of supplemental applications in 
proposed Sec. Sec.  314.60 and 314.110 necessitate a change to Sec.  
314.71, which addresses procedures for submission of supplements to 
approved applications. Current Sec.  314.71(c) states that all 
procedures and actions that apply to applications under part 314, 
including actions by applicants and the agency, also apply to 
supplements. Under proposed Sec. Sec.  314.60 and 314.110, a certain 
type of NDA supplement (i.e., efficacy supplements) will be treated the 
same as an NDA, while other types will be treated differently. To 
reflect this different treatment of certain supplements, we propose to 
revise Sec.  314.71(c) to clarify that all procedures and actions that 
apply to applications under part 314 also apply to supplements ``except 
as specified otherwise in this part.''
3. Amendments to Unapproved ANDAs (Proposed Sec.  314.96)
    Our regulations on submitting amendments to unapproved abbreviated 
applications are set forth in Sec.  314.96. Current Sec.  314.96(a)(2) 
states that submission of an amendment containing significant data or 
information constitutes an agreement to extend the review period only 
for the time necessary to review the information and for no more than 
180 days. Under Sec.  314.96(a)(3), the submission of an amendment 
containing significant data or information to resolve deficiencies 
specified in a not approvable letter will extend the date by which we 
must reach a decision on the abbreviated

[[Page 43361]]

application only for the time necessary to review the information and 
for no more than 180 days.
    We propose to revise Sec.  314.96(a)(2) to substitute the term 
``initial review cycle'' for ``review period.'' Our proposed revision 
would also clarify that an amendment to an ANDA submitted before the 
end of the initial review cycle that contains significant data or 
information could extend the initial review cycle for as many as 180 
days. Thus, we are proposing to retain the Office of Generic Drugs' 
current approach to amendments to ANDAs.
    We propose to delete Sec.  314.96(a)(3) because the submission of 
an amendment to an abbreviated application following receipt of a 
complete response letter (i.e., a resubmission of an abbreviated 
application) is addressed in proposed Sec.  314.110.

IV. Analysis of Economic Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act (Public Law 104-4). Executive Order 
12866 directs agencies to assess all costs and benefits of available 
regulatory alternatives and, when regulation is necessary, to select 
regulatory approaches that maximize net benefits (including potential 
economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is not a significant regulatory action as defined by 
the Executive order.
    The Regulatory Flexibility Act requires agencies to prepare a 
Regulatory Flexibility Analysis for each rule unless the agency 
certifies that the rule will not have a significant economic impact on 
a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule includes 
any Federal mandate that may result in the expenditure by State, local, 
and tribal governments, in the aggregate, or by the private sector, of 
$100,000,000 or more (adjusted annually for inflation) in any one year.
    We believe that this proposed rule is consistent with the 
regulatory philosophy and principles identified in Executive Order 
12866. Because the proposed rule does not impose mandates on State, 
local, or tribal governments, or the private sector, that would result 
in an expenditure in any one year of $100,000,000 or more, we are not 
required to perform a cost-benefit analysis under the Unfunded Mandates 
Reform Act of 1995.
    With respect to the Regulatory Flexibility Act, we do not believe 
that this proposed rule would have a significant economic impact on a 
substantial number of small entities. We are taking this action to 
amend our regulations governing applications for approval to market new 
drugs, generic drugs, and biological products. This action is necessary 
to meet a user fee performance goal to replace approvable and not 
approvable letters with complete response letters. The proposed rule 
also would revise regulations governing amendments to unapproved 
applications and codify terminology used in user fee performance goals 
affecting resubmissions of applications. As discussed in greater detail 
in the following paragraphs, the economic impact of these regulatory 
changes is not expected to be significant for any affected entity.

A. Impact of the Proposed Rule

    As described in detail in sections II and III of this document, the 
proposed rule would do the following: (1) For NDAs and ANDAs, replace 
the two types of action letters currently used (approvable and not 
approvable letters) with complete response letters; (2) for BLAs, 
incorporate into the regulations an existing policy on complete 
response letters; (3) incorporate into regulations the terminology and 
procedures used in the user fee performance goals regarding NDA 
resubmissions; and (4) revise regulations governing extension of the 
initial review cycle in response to major amendments to unapproved 
applications, supplements, and resubmissions. For NDAs (with respect to 
resubmissions and amendments) and BLAs, the proposed rule largely would 
codify current agency practices. For ANDAs, the proposed rule would 
revise regulations to be consistent with current practice or, where 
appropriate, with the provisions governing NDAs. The most significant 
impact of the proposed rule would be on efficacy supplements to 
approved NDAs and on resubmissions of applications and efficacy 
supplements. The impact of specific provisions of this proposed rule on 
NDAs, ANDAs, efficacy supplements, and resubmissions is described in 
greater detail in the following paragraphs.
1. Complete Response Letter
    We are proposing regulatory changes that would replace approvable 
and not approvable letters with complete response letters. Both 
approvable and not approvable letters indicate that an NDA or ANDA is 
not approvable in its current form, and that changes are necessary or 
that we require additional information. A complete response letter 
would describe the deficiencies in an NDA or ANDA and, where 
appropriate, the actions necessary to place the application in 
condition for approval. In the past, some drug manufacturers have 
expressed concern that a not approvable letter sends an unintended 
message that a marketing application will never be approved, which 
could adversely affect a company's ability to raise capital. Thus, in 
addition to allowing us to meet our commitments under the user fee 
performance goals, this regulatory change addresses industry comments 
by adopting a more neutral mechanism to convey that an NDA or ANDA 
cannot be approved in its current form. (We have already adopted a 
policy of issuing complete response letters for BLAs, and the proposed 
rule would simply codify this policy.) Because this regulatory change 
is primarily administrative in nature and is being made in response to 
the user fee performance goals, it is expected to have little or no 
economic impact.
2. Resubmissions
    We also are proposing regulatory changes to implement the user fee 
performance goals and to codify new terminology associated with the 
resubmission of drug marketing applications. A Class 2 resubmission 
(incorporating major changes or a significant amount of additional 
data) would start a new 6-month review cycle, whereas a Class 1 
resubmission (incorporating minor changes or a limited amount of 
additional data) would begin a new 2-month review cycle. These changes 
would codify agency practices regarding NDA resubmissions in place 
since 1998.
    We are proposing to apply the Class 1 and Class 2 provisions to 
resubmissions of efficacy supplements as well. We agreed to make this 
policy change in PDUFA III because efficacy supplements, like original 
NDAs, contain varying amounts of data requiring different review times. 
We began to implement this change in October 2002. The proposed 
application of the Class 1 and Class 2 provisions to resubmissions of 
efficacy supplements would represent a regulatory change because under 
PDUFA II, all resubmissions of efficacy supplements would start a new 
6-month review cycle. Under the proposed rule, a Class 1 resubmission 
of an efficacy supplement would extend the review

[[Page 43362]]

cycle by only 2 months, rather than 6 months, as occurred under PDUFA 
II. Review times for Class 2 efficacy supplement resubmissions would be 
largely unaffected by the proposed change. Based on data from 1996 to 
2000 (the most recent 5-year period for which complete data were 
available), an average of 16 efficacy supplements (approximately 40 
percent) resubmitted annually would be reviewed in 2 months rather than 
the current 6 months. The proposed rule generally would maintain 
current agency practice (review within 6 months) with respect to the 
review of other types of NDA supplements, i.e., for CMC or labeling 
changes (although under PDUFA III, our goal is to review within 4 
months resubmissions of certain CMC supplements for which prior 
approval is required). For ANDA resubmissions, the proposal would 
codify the current practice of 6-month review.
3. Amendments to Unapproved Drug Marketing Applications
    We also are proposing to revise our regulations on extending the 
initial review cycle following the submission of an amendment to an 
unapproved drug marketing application. Current regulations state, for 
unapproved NDAs and efficacy supplements, that submission of a major 
amendment extends the review cycle for the amount of time necessary to 
review the new information but not by more than 180 days. The proposed 
rule generally would extend the review cycle by 3 months if a major 
amendment to an application, efficacy supplement, or resubmission of an 
application or efficacy supplement were submitted within 3 months of 
the end of the initial review cycle. (The proposed rule states that we 
may defer review until a subsequent review cycle.) If a major amendment 
were submitted more than 3 months before the end of the initial review 
cycle, the review cycle would not be extended. These changes would 
codify the practice for NDAs that has been in place since 1998. 
However, we have recently begun to apply this policy to efficacy 
supplements. Before October 2002, under the user fee performance goals, 
we did not extend the review cycle for a major amendment to an efficacy 
supplement. Therefore, as with the proposed change regarding 
resubmissions of efficacy supplements, we believe that it is 
appropriate to treat the proposed change regarding amendments to 
unapproved efficacy supplements as a regulatory change for purposes of 
this analysis.
    These provisions of the proposed rule might slightly increase 
review times for efficacy supplements for which at least one major 
amendment was received during the initial review cycle. Based on data 
from 1996 to 2000, these regulatory changes could affect as many as 11 
percent of all efficacy supplements filed or an average of 15 per year. 
The effect of this change is dependent on the timing of future filings 
and the number of instances in which we might exercise our review 
discretion.
    With respect to amendments to ANDAs, the proposed changes to 
regulations would codify FDA's current approach.

B. Summary of Impacts

    Based on the preceding analysis, the proposed changes to provisions 
governing resubmissions could result in reduced review times for up to 
40 percent of efficacy supplements resubmitted annually. However, the 
proposed provisions governing major amendments could slightly increase 
review times for up to 11 percent of efficacy supplements (for which at 
least one major amendment was received during the initial review cycle) 
filed annually. The full impact of this rule would be affected by the 
number of future submissions and the extent to which we might exercise 
our discretion to defer review until the next cycle. ANDAs will not be 
significantly affected by the proposed changes to regulations.
    Because this proposed rule generally amends current regulations 
governing applications for approval to market new drugs and generic 
drugs to reflect user fee terminology and performance goals that have 
already been incorporated into FDA policies (except with respect to 
complete response letters, as previously noted), we certify that the 
proposed rule will not have a significant economic impact on a 
substantial number of small entities. Therefore, no further analysis is 
required under the Regulatory Flexibility Act.

V. Environmental Impact

    We have determined under 21 CFR 25.30(h) that this action is of a 
class of actions that do not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

VI. Paperwork Reduction Act of 1995

    This proposed rule does not contain new information collection 
provisions that are subject to review by the Office of Management and 
Budget (OMB) under the Paperwork Reduction Act of 1995 (the PRA) (44 
U.S.C. 3501-3520). The proposed rule would substitute complete response 
letters for approvable and not approvable letters (in current 
Sec. Sec.  314.110 and 314.120, respectively) when we take action on 
marketing applications. The proposed rule would retain the provisions 
requiring the recipient of the action letter (a complete response 
letter under the proposed rule) to either amend the application 
(resubmit it), withdraw it, or ask us to provide an opportunity for a 
hearing on whether there are grounds for denying approval of the 
application. The proposed rule also would revise the regulations 
(Sec. Sec.  314.60, 314.96, 314.110, and 314.120) on extending the 
review cycle due to the submission of amendments before we issue an 
action letter and due to resubmissions, but would not change the 
information required in such amendments and resubmissions. OMB has 
approved the information collection previously discussed concerning 
responses to action letters under OMB control number 0910-0001, which 
expires on March 31, 2005.
    The proposed rule would also establish regulations on the issuance 
of complete response letters to biologics license applicants and 
supplement applicants. The proposed rule would codify current agency 
practice on the issuance of complete response letters to these 
applicants and on applicant actions in response to these letters 
(resubmission or withdrawal of the application or supplement). OMB has 
already approved the information collection concerning responses to 
complete response letters for BLAs and BLA supplements under OMB 
control number 0910-0338, which expires on August 31, 2005.
    FDA tentatively concludes that this proposed rule contains no new 
collection of information. Therefore, OMB clearance under the PRA is 
not required.

VII. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have determined that 
the rule does not contain policies that have substantial direct effects 
on the States, on the relationship between the National Government and 
the States, or on the distribution of power and responsibilities among 
the various levels of government. Accordingly, we have concluded that 
the rule does not contain policies that have federalism implications as 
defined in the order and, consequently, a federalism summary impact 
statement is not required.

[[Page 43363]]

VIII. Proposed Effective Date

    We propose that any final rule that may issue based on this 
proposal become effective 30 days after the date of its publication in 
the Federal Register.

IX. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments on this proposal. Submit 
a single copy of electronic comments or two paper copies of any mailed 
comments, except that individuals may submit one paper copy. Comments 
are to be identified with the docket number found in brackets in the 
heading of this document. Received comments may be seen in the Division 
of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects

21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, Reporting and recordkeeping requirements, Safety.

21 CFR Part 314

    Administrative practice and procedure, Confidential business 
information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 312, 314, 600, and 601 be amended as 
follows:

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

    1. The authority citation for 21 CFR part 312 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371; 42 
U.S.C. 262.

    2. Section 312.84 is amended in paragraph (c) by revising the first 
sentence to read as follows:


Sec.  312.84  Risk-benefit analysis in review of marketing applications 
for drugs to treat life-threatening and severely-debilitating 
illnesses.

* * * * *
    (c) If FDA concludes that the data presented are not sufficient for 
marketing approval, FDA will issue a complete response letter under 
Sec.  314.110 of this chapter (for a drug) or Sec.  601.3 of this 
chapter (for a biologic). * * *
* * * * *

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG

    3. The authority citation for 21 CFR part 314 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 355a, 356, 
356a, 356b, 356c, 371, 374, 379e.

    4. Section 314.3 is amended in paragraph (b) by removing the 
definitions for ``Approvable letter'' and ``Not approvable letter'' and 
by adding the following definitions in alphabetical order:


Sec.  314.3  Definitions.

* * * * *
    (b) * * *
    Class 1 resubmission means the resubmission of an application, 
following receipt of a complete response letter, that contains final 
printed labeling, draft labeling, certain safety updates, stability 
updates to support provisional or final dating periods, commitments to 
perform Phase 4 studies (including proposals for such studies), assay 
validation data, final release testing on the last lots used to support 
approval, minor reanalyses of previously submitted data, and other 
comparatively minor information.
    Class 2 resubmission means the resubmission of an application, 
following receipt of a complete response letter, that includes any item 
not specified in the definition of ``Class 1 resubmission,'' including 
any item that would require presentation to an advisory committee.
    Complete response letter means a written communication to an 
applicant from FDA usually identifying all of the deficiencies in an 
application or abbreviated application that must be satisfactorily 
addressed before it can be approved.
* * * * *
    Efficacy supplement means a supplement to an approved application 
to make one or more of the following changes to product labeling:
    (1) Add or modify an indication for use;
    (2) Revise the dose or dose regimen;
    (3) Provide for a new route of administration;
    (4) Make a comparative efficacy claim naming another drug product;
    (5) Significantly alter the intended patient population;
    (6) Change the marketing status from prescription to over-the-
counter use;
    (7) Complete the traditional approval of a product originally 
approved under subpart H of this part or;
    (8) Incorporate other information based on at least one adequate 
and well-controlled clinical study.
* * * * *
    Original application means a pending application for which FDA has 
never issued a complete response letter or approval letter, or an 
application that was submitted again after FDA had refused to file it 
or after it was withdrawn without being approved.
* * * * *


Sec.  314.50  [Amended]

    5. Section 314.50 is amended in paragraph (d)(5)(vi)(b) in the 
fourth sentence by removing the phrase ``following receipt of an 
approvable letter'' and by adding in its place the phrase ``in a 
resubmission following receipt of a complete response letter''.
    6. Section 314.60 is amended as follows:
    a. By revising the section heading;
    b. By revising paragraph (a);
    c. By redesignating paragraphs (b) and (c) as paragraphs (c) and 
(d), respectively;
    d. By adding new paragraph (b); and
    e. By revising newly redesignated paragraphs (c)(1)(iii) and 
(c)(1)(iv), and the first sentence of paragraph (c)(2) to read as 
follows:


Sec.  314.60  Amendments to an unapproved application, supplement, or 
resubmission.

    (a) FDA generally assumes that when an original application, 
supplement to an approved application, or resubmission of an 
application or supplement is submitted to the agency for review, the 
applicant believes that the agency can approve the application, 
supplement, or resubmission as submitted. However, the applicant may 
submit an amendment to an application that has been filed under Sec.  
314.101 but is not yet approved.
    (b)(1) Submission of a major amendment to an original application, 
efficacy supplement, or resubmission of an application or efficacy 
supplement within 3 months of the end of the initial review cycle 
constitutes an agreement by the applicant under section 505(c) of the 
act to extend the initial review cycle by 3 months. FDA may instead 
defer review of the amendment until the subsequent review cycle. If the 
agency extends the initial review cycle for an original application, 
efficacy supplement, or resubmission under this paragraph, the division 
responsible for reviewing the application, supplement,

[[Page 43364]]

or resubmission will notify the applicant of the extension. The initial 
review cycle for an original application, efficacy supplement, or 
resubmission of an application or efficacy supplement may be extended 
only once due to submission of a major amendment. FDA may, at its 
discretion, review any subsequent major amendment during the initial 
review cycle (as extended) or defer review until the subsequent review 
cycle.
    (2) Submission of a major amendment to an original application, 
efficacy supplement, or resubmission of an application or efficacy 
supplement more than 3 months before the end of the initial review 
cycle will not extend the cycle. FDA, may, at its discretion, review 
such an amendment during the initial review cycle or defer review until 
the subsequent review cycle.
    (3) Submission of an amendment to an original application, efficacy 
supplement, or resubmission of an application or efficacy supplement 
that is not a major amendment will not extend the initial review cycle. 
FDA may, at its discretion, review such an amendment during the initial 
review cycle or defer review until the subsequent review cycle.
    (4) Submission of an amendment to a supplement other than an 
efficacy supplement will not extend the initial review cycle. FDA may, 
at its discretion, review such an amendment during the initial review 
cycle or defer review until the subsequent review cycle.
    (5) A major amendment may not include data to support an indication 
for a use that was not included in the original application, 
supplement, or resubmission.
    (c)(1) * * *
    (iii) The applicant has not obtained a right of reference to the 
investigation described in paragraph (c)(1)(ii) of this section; and
    (iv) The report of the investigation described in paragraph 
(c)(1)(ii) of this section would be essential to the approval of the 
unapproved application.
    (2) The submission of an amendment described in paragraph (c)(1) of 
this section will cause the unapproved application to be deemed to be 
withdrawn by the applicant under Sec.  314.65 on the date of receipt by 
FDA of the amendment.* * *
* * * * *
    7. Section 314.65 is amended by revising the second sentence to 
read as follows:


Sec.  314.65  Withdrawal by the applicant of an unapproved application.

    * * * If, by the time it receives such notice, the agency has 
identified any deficiencies in the application, we will list such 
deficiencies in the letter we send the applicant acknowledging the 
withdrawal.* * *


Sec.  314.71  [Amended]

    8. Section 314.71 is amended in paragraph (c) by adding the phrase 
``except as specified otherwise in this part'' at the end of the 
sentence.


Sec.  314.96  [Amended]

    9. Section 314.96 is amended by revising paragraph (a)(2) and by 
removing paragraph (a)(3) to read as follows:


Sec.  314.96  Amendments to an unapproved abbreviated application.

    (a) * * *
    (2) Submission of an amendment containing significant data or 
information before the end of the initial review cycle constitutes an 
agreement between FDA and the applicant to extend the initial review 
cycle only for the time necessary to review the significant data or 
information and for no more than 180 days.
* * * * *
    10. Section 314.100 is revised to read as follows:


Sec.  314.100  Timeframes for reviewing applications and abbreviated 
applications.

    (a)(1) Except as provided in paragraph (a)(2) of this section, 
within 180 days of receipt of an application for a new drug under 
section 505(b) of the act or an abbreviated application for a new drug 
under section 505(j) of the act, FDA will review it and send the 
applicant either an approval letter under Sec.  314.105 or a complete 
response letter under Sec.  314.110. This 180-day period is called the 
``initial review cycle.''
    (2) For applications that are human drug applications, as defined 
in section 735(1)(A) and (B) of the act, or supplements to such 
applications, as defined in section 735(2) of the act, the initial 
review cycle will be adjusted to be consistent with the agency's user 
fee performance goals for reviewing such applications and supplements.
    (b) At any time before approval, an applicant may withdraw an 
application under Sec.  314.65 or an abbreviated application under 
Sec.  314.99 and later submit it again for consideration.
    (c) The review cycle may be extended by mutual agreement between 
FDA and an applicant or as provided in Sec. Sec.  314.60 and 314.96, as 
the result of a major amendment.
    11. Section 314.101 is amended as follows:
    a. By revising paragraph (f)(1)(ii);
    b. By redesignating paragraphs (f)(2) and (f)(3) as paragraphs 
(f)(3) and (f)(4), respectively;
    c. By adding new paragraph (f)(2); and
    d. By revising the second sentence of newly redesignated paragraph 
(f)(3) to read as follows:


Sec.  314.101  Filing an application and receiving an abbreviated new 
drug application.

* * * * *
    (f)(1) * * *
    (ii) Issue a notice of opportunity for hearing if the applicant 
asked FDA to provide it an opportunity for a hearing on an application 
in response to a complete response letter.
    (2) For applications that are human drug applications, as defined 
in section 735(1)(A) and (B) of the act, or supplements to such 
applications, as defined in section 735(2) of the act, the 180-day 
period specified in paragraph (f)(1) of this section will be adjusted 
to be consistent with the agency's user fee performance goals for 
reviewing such applications and supplements.
    (3) * * * If FDA disapproves the abbreviated new drug application, 
FDA will issue a notice of opportunity for hearing if the applicant 
asked FDA to provide it an opportunity for a hearing on an abbreviated 
new drug application in response to a complete response letter.
* * * * *
    12. Section 314.102 is amended in the last sentence in paragraph 
(b) by removing the phrase ``an action'' and adding in its place the 
phrase ``a complete response'' and by revising paragraph (d) to read as 
follows:


Sec.  314.102  Communications between FDA and applicants.

* * * * *
    (d) End-of-review conference. At the conclusion of FDA's review of 
an NDA as designated by the issuance of a complete response letter, FDA 
will provide the applicant with an opportunity to meet with agency 
reviewing officials. The purpose of the meeting will be to discuss what 
further steps need to be taken by the applicant before the application 
can be approved. Requests for such meetings must be directed to the 
director of the division responsible for reviewing the application.
* * * * *


Sec.  314.103  [Amended]

    13. Section 314.103 is amended in paragraph (c)(1) in the first 
sentence by removing the phrase ``an approvable or not approvable'' and 
adding in its place the phrase ``a complete response'' and

[[Page 43365]]

by removing the phrase ``or Sec.  314.120, respectively''.


Sec.  314.105  [Amended]

    14. Section 314.105 is amended in paragraph (b) in the first 
sentence by removing the phrase ``(rather than an approvable letter 
under Sec.  314.110)''.
    15. Section 314.107 is amended by adding a new sentence at the 
beginning of paragraph (b)(3)(v) to read as follows:


Sec.  314.107  Effective date of approval of a 505(b)(2) application or 
abbreviated new drug application under section 505(j) of the act.

* * * * *
    (b) * * *
    (3) * * *
    (v) FDA will issue a tentative approval letter when tentative 
approval is appropriate in accordance with paragraph (b)(3) of this 
section.* * *
* * * * *
    16. Section 314.110 is revised to read as follows:


Sec.  314.110  Complete response letter to the applicant.

    (a) Complete response letter. FDA will send the applicant a 
complete response letter if the agency determines that we will not 
approve the application or abbreviated application in its present form 
for one or more of the reasons given in Sec.  314.125 or Sec.  314.127, 
respectively.
    (1) Description of specific deficiencies. A complete response 
letter will describe all of the specific deficiencies in an application 
or abbreviated application, except as stated in paragraph (a)(3) of 
this section.
    (2) Complete review of data. A complete response letter reflects 
FDA's complete review of the data submitted in an original application 
or abbreviated application (or, where appropriate, a resubmission) and 
any amendments for which the review cycle was extended. The complete 
response letter will identify any amendments for which the review cycle 
was not extended that FDA has not yet reviewed.
    (3) Inadequate data. If FDA determines, after an application is 
filed or an abbreviated application is received, that the data 
submitted are inadequate to support approval, the agency might issue a 
complete response letter without first conducting required inspections 
and/or reviewing proposed product labeling.
    (4) Description of actions necessary for approval. Where 
appropriate, a complete response letter will describe the actions 
necessary to place the application or abbreviated application in 
condition for approval.
    (b) Applicant actions. After receiving a complete response letter, 
the applicant must take one of following actions:
    (1) Resubmission. Resubmit the application or abbreviated 
application, addressing all deficiencies identified in the complete 
response letter. For purposes of this section, a resubmission means 
submission by the applicant of all materials needed to fully address 
all deficiencies identified in the complete response letter.
    (i) A resubmission of an application or efficacy supplement that 
FDA classifies as a Class 1 resubmission constitutes an agreement by 
the applicant to start a new 2-month review cycle beginning on the date 
FDA receives the resubmission.
    (ii) A resubmission of an application or efficacy supplement that 
FDA classifies as a Class 2 resubmission constitutes an agreement by 
the applicant to start a new 6-month review cycle beginning on the date 
FDA receives the resubmission.
    (iii) A resubmission of an NDA supplement other than an efficacy 
supplement constitutes an agreement by the applicant to start a new 6-
month review cycle beginning on the date FDA receives the resubmission.
    (iv) A major resubmission of an abbreviated application constitutes 
an agreement by the applicant to start a new 6-month review cycle 
beginning on the date FDA receives the resubmission.
    (v) A minor resubmission of an abbreviated application constitutes 
an agreement by the applicant to start a new review cycle beginning on 
the date FDA receives the resubmission.
    (2) Withdrawal. Withdraw the application or abbreviated 
application. A decision to withdraw an application or abbreviated 
application is without prejudice to a subsequent submission.
    (3) Request opportunity for hearing. Ask the agency to provide the 
applicant an opportunity for a hearing on the question of whether there 
are grounds for denying approval of the application or abbreviated 
application under section 505(d) or (j)(4) of the act, respectively. 
The applicant must submit the request to the Associate Director for 
Policy, Center for Drug Evaluation and Research (HFD-5), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857. Within 60 days 
of the date of the request for an opportunity for a hearing, or within 
a different time period to which FDA and the applicant agree, the 
agency will either approve the application or abbreviated application 
under Sec.  314.105, or refuse to approve the application under Sec.  
314.125 or abbreviated application under Sec.  314.127 and give the 
applicant written notice of an opportunity for a hearing under Sec.  
314.200 and section 505(c)(1)(B) or (j)(5)(c) of the act on the 
question of whether there are grounds for denying approval of the 
application under section 505(d) or (j)(4) of the act.
    (c) Failure to take action. An applicant agrees to extend the 
review period under section 505(c)(1) of the act until it takes any of 
the actions listed in paragraph (b) of this section. For an 
application, FDA may consider an applicant's failure to take any of 
such actions within 1 year after receiving a complete response letter 
to be a request by the applicant to withdraw the application. For an 
abbreviated application, FDA may consider an applicant's failure to 
take any of the actions listed in paragraph (b) of this section within 
6 months after receiving a complete response letter to be a request by 
the applicant to withdraw the abbreviated application.


Sec.  314.120  [Removed and Reserved]

    17. Section 314.120 is removed and reserved.


Sec.  314.125  [Amended]

    18. Section 314.125 is amended in paragraph (a)(1) by removing the 
phrase ``an approvable or a not approvable'' and adding in its place 
the phrase ``a complete response''; and by removing the phrase ``or 
Sec.  314.120''.


Sec.  314.430  [Amended]

    19. Section 314.430 is amended by in paragraph (b) in the first 
sentence by removing the phrase ``approvable letter is sent to the 
applicant under Sec.  314.110'' and adding in its place the phrase 
``approval letter is sent to the applicant under Sec.  314.105 or 
tentative approval letter is sent to the applicant under Sec.  
314.107''; and by removing the last sentence.
    20. Section 314.440 is amended in paragraph (a)(1) by removing the 
phrase ``Document and Records Section, 5901-B Ammendale Rd., 
Beltsville, MD 20705-1266'' and by adding in its place the phrase 
``Central Document Room, 12229 Wilkins Ave., Rockville, MD 20852-
1833''; in paragraph (a)(3) by removing the phrase ``or Sec.  
314.120''; and by revising the introductory text of paragraph (b) to 
read as follows:


Sec.  314.440  Addresses for applications and abbreviated applications.

* * * * *
    (b) Applicants must send applications and other correspondence 
relating to matters covered by this part for the drug products listed 
below to the Center for Biologics Evaluation and Research (HFM-99), 
Food and Drug

[[Page 43366]]

Administration, 1401 Rockville Pike, Rockville, MD 20852, except 
applicants must send a request for an opportunity for a hearing under 
Sec.  314.110 on the question of whether there are grounds for denying 
approval of an application to the Director, Center for Biologics 
Evaluation and Research (HFM-1), at the same address.
* * * * *

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    21. The authority citation for 21 CFR part 600 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 
374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.

    22. Section 600.3 is amended by revising paragraph (jj) to read as 
follows:


Sec.  600.3  Definitions.

* * * * *
    (jj) Complete response letter means a written communication to an 
applicant from FDA usually identifying all of the deficiencies in a 
biologics license application or supplement that must be satisfactorily 
addressed before it can be approved.
* * * * *

PART 601--LICENSING

    23. The authority for 21 CFR part 601 continues to read as follows:

    Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 356b, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 
216, 241, 262, 263, 264; sec 122, Pub. L. 105-115, 111 Stat. 2322 
(21 U.S.C. 355 note).

    24. Section 601.3 is added to subpart A to read as follows:


Sec.  601.3  Complete response letter to the applicant.

    (a) Complete response letter. The Food and Drug Administration will 
send the biologics license applicant or supplement applicant a complete 
response letter if the agency determines that it will not approve the 
biologics license application or supplement in its present form.
    (b) Applicant actions. After receiving a complete response letter, 
the biologics license applicant or supplement applicant must take 
either of the following actions:
    (1) Resubmission. Resubmit the application or supplement, 
addressing all deficiencies identified in the complete response letter.
    (2) Withdrawal. Withdraw the application or supplement. A decision 
to withdraw the application or supplement is without prejudice to a 
subsequent submission.
    (c) Failure to take action. FDA may consider a biologics license 
applicant or supplement applicant's failure to either resubmit or 
withdraw the application or supplement within 1 year after receiving a 
complete response letter to be a request by the applicant to withdraw 
the application or supplement.

    Dated: July 9, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-16476 Filed 7-19-04; 8:45 am]

BILLING CODE 4160-01-S